Single-cell transcriptomic profiling of human knee cartilage reveals branching chondrocyte state transitions and extracellular matrix–centered remodeling in osteoarthritis
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Background
Osteoarthritis cartilage contains heterogeneous chondrocyte states, but molecular programs linked to state transitions within human cartilage remain incompletely resolved using public single-cell data.
Methods
A retrospective reanalysis was conducted of a public human knee cartilage single-cell RNA sequencing dataset (GSE255460) including 8 osteoarthritis donors and 3 non-osteoarthritis donors (19 samples). Cells underwent sample-wise quality control and doublet removal, followed by batch-corrected clustering, chondrocyte subclustering with marker-based annotation, and trajectory inference using Slingshot. Regulatory chondrocytes were prioritized for osteoarthritis versus control differential expression, with downstream Gene Ontology/KEGG enrichment (Benjamini–Hochberg false discovery rate <0.05) and protein–protein interaction network hub screening.
Results
After quality control, 27,036 cells were retained. Chondrocytes formed multiple transcriptional states with branching-like continuous relationships, and regulatory chondrocytes localized near the main manifold and adjacent to multiple inferred branches, consistent with a transition-adjacent state. In regulatory chondrocytes, osteoarthritis versus control differential expression was enriched for collagen-containing extracellular matrix and extracellular matrix organization, endoplasmic reticulum lumen–associated secretory/proteostasis processes, cell–matrix adhesion (including focal adhesion), and transforming growth factor beta/SMAD-related signaling. Protein–protein interaction analysis of regulatory-chondrocyte differential genes identified five high-connectivity hub genes: COL5A1, COL5A2, COL6A1, COL1A2, and COL3A1.
Conclusion
This public-dataset reanalysis supports a transition-adjacent regulatory chondrocyte program in osteoarthritis characterized by coordinated extracellular matrix remodeling with concurrent secretory/proteostasis and adhesion–transforming growth factor beta signatures, nominating collagen-network hubs as candidates for downstream validation.
